-
Frontiers in Genetics 2023Hereditary necrotizing myelopathy (HNM) in young Kooiker dogs is characterized by progressive ataxia and paralysis with autosomal recessive inheritance. The basic...
Hereditary necrotizing myelopathy (HNM) in young Kooiker dogs is characterized by progressive ataxia and paralysis with autosomal recessive inheritance. The basic genetic defect is unknown. We investigated the possible cause by a genome-wide analysis using six affected and 17 unrelated unaffected Kooiker dogs and by functional follow-up studies. The HNM locus was mapped by a case-control study using a dense SNP array and confirmed by linkage analysis of two pedigrees. The gene exons in the critical region were analyzed by next-generation sequencing. The functional effect of the candidate canine pathogenic variant was biochemically examined in an established HeLa cell culture model in which the endogenous gene product was depleted by RNAi. The basic defect was localized in the centromeric 5 Mb region of canine chromosome 14. The most associated SNP co-segregated fully with HNM and reached an LOD score of 6.1. A candidate pathogenic mutation was found in the iron-sulfur cluster assembly gene and led to the amino acid substitution R147W. The expression of human IBA57 harboring the canine R147W exchange could only partially restore the biochemical defects of several mitochondrial [4Fe-4S] proteins upon IBA57 depletion, showing that the mutant protein is functionally impaired. Pathogenic variants in human cause multiple mitochondrial dysfunction syndrome 3 (MMDS3), a neurodegenerative disorder with distant similarities to HNM. The incomplete functional complementation of IBA57-depleted human cells by IBA57-R147W identifies the DNA mutation in affected Kooiker dogs as the genetic cause of HNM. Our findings further expand the phenotypic spectrum of pathogenic variants.
PubMed: 37588046
DOI: 10.3389/fgene.2023.1190222 -
NPJ Genomic Medicine Aug 2023Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive...
Genomic sequences residing within introns of few genes have been shown to act as enhancers affecting expression of neighboring genes. We studied an autosomal recessive phenotypic continuum of microphthalmia, anophthalmia and ocular coloboma, with no apparent coding-region disease-causing mutation. Homozygosity mapping of several affected Jewish Iranian families, combined with whole genome sequence analysis, identified a 0.5 Mb disease-associated chromosome 2q35 locus (maximal LOD score 6.8) harboring an intronic founder variant in NHEJ1, not predicted to affect NHEJ1. The human NHEJ1 intronic variant lies within a known specifically limb-development enhancer of a neighboring gene, Indian hedgehog (Ihh), known to be involved in eye development in mice and chickens. Through mouse and chicken molecular development studies, we demonstrated that this variant is within an Ihh enhancer that drives gene expression in the developing eye and that the identified variant affects this eye-specific enhancer activity. We thus delineate an Ihh enhancer active in mammalian eye development whose variant causes human microphthalmia, anophthalmia and ocular coloboma. The findings highlight disease causation by an intronic variant affecting the expression of a neighboring gene, delineating molecular pathways of eye development.
PubMed: 37580330
DOI: 10.1038/s41525-023-00364-x -
Alzheimer Disease and Associated...Executive function (EF) involves a general cognitive process linked to strategic organization and control of complex goal-oriented tasks. In young-onset dementia (YOD),...
INTRODUCTION
Executive function (EF) involves a general cognitive process linked to strategic organization and control of complex goal-oriented tasks. In young-onset dementia (YOD), especially Alzheimer's disease, the symptoms that stand out in the initial stage are deficits in attention, visual-spatial function, praxis, and language. The present study aims to investigate what components of EF differ in young and late-onset dementia (LOD) and its impact on awareness and its domains.
METHODS
Using a cross-sectional design, we included 44 people with YOD and 70 with LOD. We assessed awareness and its domains, cognition, dementia severity, EF, functionality, and neuropsychiatric symptoms.
RESULTS
The YOD group was more impaired in general cognition ( P =0.017) and had a worse performance in Wechsler Digit Span Backward (DSB) ( P =0.007) and Phonemic fluency task (FAS) ( P =0.046) tests. In the LOD group, deficits in EF had a greater impact on awareness and on most domains (awareness total score, cognitive functioning and health condition, functional activity impairments and social function).
CONCLUSIONS
Our study findings support the heterogeneity of awareness, not only with regard to the difference between the domains and the measures of EF, but also to the groups studied.
Topics: Humans; Dementia; Executive Function; Cross-Sectional Studies; Age of Onset; Alzheimer Disease
PubMed: 37561987
DOI: 10.1097/WAD.0000000000000561 -
Analytical and Bioanalytical Chemistry Oct 2023Emerging polycyclic aromatic nitrogen heterocycles (PANHs) contributes significantly to the health risk associated with inhaling polluted air. However, there is a lack...
Emerging polycyclic aromatic nitrogen heterocycles (PANHs) contributes significantly to the health risk associated with inhaling polluted air. However, there is a lack of analytical methods with the needed performance to their determination. This study presents the optimization and validation for the first time of a green microscale extraction procedure for the determination of twenty-one PANHs, including carbazole, indole, and quinolone classes, in particulate matter (PM) samples by gas chromatography-mass spectrometry. A simplex-centroid mixture design and full factorial design (2) were employed to optimize the following extraction parameters: type and volume of solvent, sample size, extraction time, and necessity of a cleanup step. Low limits of detection and quantification (LOD < 0.97 pg m and LOQ < 3.24 pg m, respectively) were obtained in terms of matrix-matched calibration. The accuracy and precision of the method were adequate, with recoveries in three levels between 73 to 120% and intraday and interday relative standard deviations from 2.0 to 12.9% and 7.3 to 18.9%, respectively. The green character of the method was evaluated using the Analytical Greenness (AGREE) tool, where a score of 0.69 was obtained, indicating a great green procedure. The method was applied to PM samples collected from sites with different characteristics; the concentrations ranged from 69.3 pg m (2-methylcarbazole) to 11,874 pg m (carbazole) for individual PANHs and from 2306 to 24,530 pg m for ∑21PANHs. Principal component analysis (PCA) and hierarchical clustering enabled discrimination of the sampling sites according to the PANHs concentrations. The score plots formed two distinct groups, one with samples containing higher concentrations of PANHs, corresponding to sites with a major influence from diesel emissions, and another group with minor PANH contents, corresponding to sites impacted by emissions from urban traffic and industrial activities.
PubMed: 37541975
DOI: 10.1007/s00216-023-04889-z -
RSC Advances Jul 2023The integration of molecular modelling simulation and electrochemical sensors is of high interest. Herein, for the first time, a portable solid-contact potentiometric...
The integration of molecular modelling simulation and electrochemical sensors is of high interest. Herein, for the first time, a portable solid-contact potentiometric electrode was designed for the sensitive determination of mirabegron (MIR) in human plasma and pharmaceutical formulation. A two-step optimization protocol was investigated for the fabrication of an ion on sensing polymeric membrane. First, molecular docking was used for optimum ionophore selection. Calix[6]arene showed the highest affinity towards MIR with a better docking score (-4.35) and potential energy (-65.23) compared to other calixarene derivatives. Second, carbon nanotubes and gold nanoparticles were investigated as ion-electron transducers using a drop-casting procedure. Gold nanoparticle-based sensors showed better slope, potential stability, and rapid response compared to carbon nanotubes. The proposed solid contact sensors (V-VII) showed comparable sensitivity and ease of handling compared to liquid contact sensors (I-IV). The optimized gold nanoparticles sensor VII produced a Nernstian response over the range of 9.77 × 10 to 1 × 10 M with LOD of 2.4 × 10 M. It has also been used to determine MIR in its pharmaceutical formulation in the presence of a co-formulated antioxidant butylated hydroxytoluene and spiked human plasma. This would offer a feasible and economic platform for monitoring MIR in pharmaceutical preparation and biological fluids.
PubMed: 37533779
DOI: 10.1039/d3ra02343e -
Frontiers in Plant Science 2023Guava ( L.) is an important fruit crop of the Indian sub-continent, with potential for improvements in quality and yield. The goal of the present study was to construct...
Guava ( L.) is an important fruit crop of the Indian sub-continent, with potential for improvements in quality and yield. The goal of the present study was to construct a genetic linkage map in an intraspecific cross between the elite cultivar 'Allahabad Safeda' and the Purple Guava landrace to identify the genomic regions responsible for important fruit quality traits, viz., total soluble solids, titratable acidity, vitamin C, and sugars. This population was phenotyped in field trials (as a winter crop) for three consecutive years, and showed moderate-to-high values of heterogeneity coefficients along with higher heritability (60.0%-97.0%) and genetic-advance-over-mean values (13.23%-31.17%), suggesting minimal environmental influence on the expression of fruit-quality traits and indicating that these traits can be improved by phenotypic selection methods. Significant correlations and strong associations were also detected among fruit physico-chemical traits in segregating progeny. The constructed linkage map consisted of 195 markers distributed across 11 chromosomes, spanning a length of 1,604.47 cM (average inter-loci distance of 8.80 markers) and with 88.00% coverage of the guava genome. Fifty-eight quantitative trait loci (QTLs) were detected in three environments with best linear unbiased prediction (BLUP) values using the composite interval mapping algorithm of the BIP (biparental populations) module. The QTLs were distributed on seven different chromosomes, explaining 10.95%-17.77% of phenotypic variance, with the highest LOD score being 5.96 for qTSS.AS.pau-6.2. Thirteen QTLs detected across multiple environments with BLUPs indicate stability and utility in a future breeding program for guava. Furthermore, seven QTL clusters with stable or common individual QTLs affecting two or more different traits were located on six linkage groups (LGs), explaining the correlation among fruit-quality traits. Thus, the multiple environmental evaluations conducted here have increased our understanding of the molecular basis of phenotypic variation, providing the basis for future high-resolution fine-mapping and paving the way for marker-assisted breeding of fruit-quality traits.
PubMed: 37426984
DOI: 10.3389/fpls.2023.1123274 -
The Plant Genome Dec 2023Malnutrition is a major challenge globally, and groundnut is a highly nutritious self-pollinated legume crop blessed with ample genomic resources, including the routine...
Malnutrition is a major challenge globally, and groundnut is a highly nutritious self-pollinated legume crop blessed with ample genomic resources, including the routine deployment of genomic-assisted breeding. This study aimed to identify genomic regions and candidate genes for high iron (Fe) and zinc (Zn) content, utilizing a biparental mapping population (ICGV 00440 × ICGV 06040;). Genetic mapping and quantitative trait locus (QTL) analysis (474 mapped single-nucleotide polymorphism loci; 1536.33 cM) using 2 seasons of phenotypic data together with genotypic data identified 5 major main-effect QTLs for Fe content. These QTLs exhibited log-of-odds (LOD) scores ranging from 6.5 to 7.4, explaining phenotypic variation (PVE) ranging from 22% (qFe-Ah01) to 30.0% (qFe-Ah14). Likewise, four major main effect QTLs were identified for Zn content, with LOD score ranging from 4.4 to 6.8 and PVE ranging from 21.8% (qZn-Ah01) to 32.8% (qZn-Ah08). Interestingly, three co-localized major and main effect QTLs (qFe-Ah01, qZn-Ah03, and qFe-Ah11) were identified for both Fe and Zn contents. These genomic regions harbored key candidate genes, including zinc/iron permease transporter, bZIP transcription factor, and vacuolar iron transporter which likely play pivotal roles in the accumulation of Fe and Zn contents in seeds. The findings of this study hold potential for fine mapping and diagnostic marker development for high Fe and Zn contents in groundnut.
Topics: Quantitative Trait Loci; Zinc; Plant Breeding; Fabaceae; Iron
PubMed: 37408143
DOI: 10.1002/tpg2.20361 -
Clinica Chimica Acta; International... Aug 2023The Enhanced Liver Fibrosis (ELF) Test comprises 3 direct serum markers of fibrosis-hyaluronic acid (HA), amino-terminal pro-peptide of type III procollagen (PIIINP),...
BACKGROUND
The Enhanced Liver Fibrosis (ELF) Test comprises 3 direct serum markers of fibrosis-hyaluronic acid (HA), amino-terminal pro-peptide of type III procollagen (PIIINP), and tissue inhibitor of matrix metalloproteinase 1 (TIMP-1)-whose results are combined in an algorithm to generate the ELF score. Outside the U.S., the ELF Test and score are CE marked for assessment of liver fibrosis severity in patients with signs, symptoms, or risk factors of chronic liver disease to support diagnosis of fibrosis staging or prognosis for likelihood of progression to cirrhosis and liver-related clinical events. In the U.S., the FDA granted de novo marketing authorization to aid prognostic evaluation of disease progression (to cirrhosis and liver-related clinical events) in nonalcoholic steatohepatitis patients with advanced liver fibrosis. We describe the analytical performance of the ELF analytes and score on the Atellica® IM Analyzer.
METHODS
Clinical and Laboratory Standards Institute protocols were followed for detection capability (limits of blank [LoB], detection [LoD], and quantitation [LoQ]), precision, interference, linearity, hook effect, and ELF reference interval.
RESULTS
All parameters met predetermined requirements: HA (LoB 1.00 ng/mL, LoD 2.00 ng/mL, LoQ 3.00 ng/mL); PIIINP (LoB 0.50 ng/mL, LoD 0.75 ng/mL, LoQ 1.00 ng/mL); TIMP-1 (LoB 3.0 ng/mL, LoD 4.0 ng/mL, LoQ 5.0 ng/mL). Across the 3 assays, repeatability was ≤5.4% CV; within-lab precision was ≤8.5% CV. ELF score repeatability was ≤0.6% CV, within-lab precision ≤1.3% CV, and reproducibility ≤1.1% CV. Good correlation was obtained between the Atellica IM ELF and ADVIA Centaur ELF Tests (y = 1.01x - 0.22, r = 0.997). Assays were linear across analytical measuring ranges.
CONCLUSIONS
Analytical performance validation results for the ELF Test and ELF score were excellent making the test acceptable for routine clinical use.
Topics: Humans; Tissue Inhibitor of Metalloproteinase-1; Reproducibility of Results; Liver Cirrhosis; Fibrosis; Liver; Biomarkers; Hyaluronic Acid
PubMed: 37390944
DOI: 10.1016/j.cca.2023.117461 -
Indian Journal of Ophthalmology Jun 2023This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
PURPOSE
This case-control study aims to examine possible associations of VSX1 exon3 gene variants with the development of keratoconus (KC) in Malaysian patients.
METHODS
A case-control study was done on 42 keratoconus cases, 127 family member controls, and 96 normal controls.
RESULTS
Three gene variants, p.A182A, p.P237P, and p.R217H showed significant associations with keratoconus (P < 0.05). While p.A182A and p.P227P were more prevalent than in the family and normal controls (OR 3.14-4.05), the reverse was observed with p.R217H (OR 0.086-1.59). With Haploview analysis, p.A182A and p.P237P were shown to be in linkage disequilibrium (LD) (LOD (logarithm of the odds score) score of 2.0, r2 of 0.957, and 95% confidence interval (CI) of 0.96-1.00).
CONCLUSION
The study results suggest that the p.A182A and p.P237P variants could have contributed to the development of keratoconus in some Malaysians and that these two variants are likely to be co-inherited. In contrast, the p.R217H variant appeared to confer some protection against the development of keratoconus.
Topics: Humans; Asian People; Case-Control Studies; Eye Proteins; Homeodomain Proteins; Keratoconus
PubMed: 37322657
DOI: 10.4103/IJO.IJO_2894_22 -
Annals of Emergency Medicine Oct 2023We examined the diagnostic performance of a recalibrated History, Electrocardiogram, Age, Risk factors, Troponin (HEART), and Thrombolysis in Myocardial Infarction...
STUDY OBJECTIVE
We examined the diagnostic performance of a recalibrated History, Electrocardiogram, Age, Risk factors, Troponin (HEART), and Thrombolysis in Myocardial Infarction (TIMI) score in patients with suspected acute cardiac syndrome (ACS). Recalibration of troponin thresholds was performed, including shifting from the 99th percentile to the limit of detection (LOD) or to the limit of quantification (LOQ) We compared the discharge potential and safety of the recalibrated composite scores using a single presentation high-sensitivity cardiac troponin (hs-cTn) T to the conventional scores and with a LOD/LOQ troponin strategy alone.
METHODS
We undertook a 2-center prospective cohort study in the United Kingdom (UK) (2018) (Clinicaltrials.gov NCT03619733) to specifically assess recalibrated risk scores (shifting the troponin subset scoring from 99th percentile to LOD [UK]) and combined the results of this with secondary analyses of 2 prospective cohort studies in the UK (2011) and the United States (2018, using LOQ rather than LOD). The primary outcome was major adverse cardiovascular events (MACE), defined as adjudicated type 1 myocardial infarction (MI), urgent coronary revascularization, and all-cause death, at 30 days. We evaluated the original scores using hs-cTn below the 99th percentile and recalibrated scores using hs-cTn <LOD/LOQ and compared these composite scores with a single hs-cTnT less than LOD/LOQ combined with a nonischemic ECG. For each discharge strategy, an assessment of clinical effectiveness was also made, defined as the proportion of patients eligible for discharge from the emergency department without the need for further inpatient testing.
RESULTS
We studied 3,752 patients (3,003 in the UK and 749 in the United States). Median age was 58 years, and 48% were female. At 30 days, 330/3,752 (8.8%) experienced MACE. The sensitivities of the original HEART less or equal to 3 and recalibrated HEART less or equal to 3 scores for rule-out were 96.1% (95% confidence interval [CI], 93.4 to 97.9) and 98.6% (95% CI, 96.5 to 99.5) respectively; the original TIMI less or equal to 1 and recalibrated TIMI less or equal to 1 scores' sensitivities were 79.7% (95% CI, 74.9 to 83.9) and 96.1% (95% CI, 93.4 to 97.9) respectively; and nonischemic ECG with hs-cTn T below the 99th percentile and hs-cTn T less than LOD/LOQ was 79.7% (95%CI, 0.749 to 0.839) and 99.1% (95% CI, 0.974 to 0.998), respectively. Recalibrated HEART less or equal to 3 was projected to discharge 14% more patients than hs-cTn T less than LOD/LOQ. The improved sensitivity of rule-out for recalibrated HEART less than or equal to 3 came at the cost of reduced specificity (50.8% versus 53.8% for recalibrated HEART and conventional HEART respectively).
CONCLUSION
This study indicates that recalibrated HEART score of less or equal to 3 is a feasible and safe early discharge strategy using a single presentation hs-cTnT. This finding should be further tested using competitor hs-cTn assays in independent prospective cohorts before implementation.
Topics: Humans; Female; Middle Aged; Male; Troponin T; Prospective Studies; Troponin; Myocardial Infarction; Acute Coronary Syndrome; Biomarkers; Emergency Service, Hospital
PubMed: 37306637
DOI: 10.1016/j.annemergmed.2023.04.024